In general, with regard to transpulmonary administration, it is known that the active ingredient contained in a medicine can be delivered into the lungs efficiently by making the mean particle diameter of the active ingredient be 10 microns or less, preferably 5 microns or less. The current situation with conventional inhalations for transpulmonary administration is thus that, to make the medicine have a particle diameter suitable for transpulmonary administration in advance, fine particles are prepared by a spray drying method, a jet milling method or the like, and possibly further processing is carried out, and then the fine particles are provided filled into a dry powder inhaler.
Specifically, Japanese Unexamined Patent Publication No. 1999-171760 discloses three types of powdered inhalation, namely (1) a preparation comprising a powder-form composition comprising only medicinal fine particles filled into a suitable vessel, (2) a preparation comprising a powder-form composition in which medicinal fine particles have been granulated gently to form a relatively large particle diameter filled into a suitable vessel, and (3) a preparation comprising a powder-form composition comprising mixed particles in which medicinal fine particles and vehicle particles (lactose etc.) having a particle diameter larger than the medicinal fine particles are mixed together uniformly filled into a suitable vessel. Moreover, it is disclosed that if these powdered inhalations are administered into the respiratory tract, then the behavior shown is that with (1) the medicinal fine particles in the composition reach the lower respiratory tract, for example the trachea and the bronchi, and are deposited here, with (2) the granulated medicine separates into fine particles in flight in the respiratory tract, and the medicinal fine particles produced reach the lower respiratory tract, for example the trachea and the bronchi, and are deposited here, and with (3) the vehicle is deposited in the oral cavity, on the pharynx or on the larynx, and the medicinal fine particles only reach the lower respiratory tract, for example the trachea and the bronchi, and are deposited here.
In this way, with a conventional powdered inhalation for transpulmonary administration, the ingredient to be inhaled is made into desirable fine particles in advance, and then these fine particles, or else these fine particles further processed by some method, are filled into a dry powder inhaler, and transpulmonary administration is carried out using this.
To make a low-molecular-weight drug into fine particles, a spray drying method (for example, a method disclosed in Japanese Unexamined Patent Publication No. 1999-171760), a jet milling method (for example, a method disclosed in Japanese Unexamined Patent Publication No. 2001-151673) or the like is usually used. The jet milling method comprises applying an air impact having an air flow rate of at least 1000 L/min and an air speed not less than the sonic speed to a low-molecular-weight drug to make the drug into fine particles. No method is known which makes the drug into fine particles by a low air impact.
For a high-molecular-weight drug such as a peptide or protein, on the other hand, for example a method in which a spray solution of a medicinal stock liquid containing additives is subjected to spray drying, thus making the stock liquid into fine particles having a mean particle diameter of 5 microns or less in one step, and then these fine particles are filled into a dry powder inhaler (spray drying method: WO 95/31479), and a method in which a peptide or protein is freeze-dried along with additives, and then the freeze-dried composition is made into fine particles by jet milling or the like, and these fine particles are filled into a dry powder inhaler (freeze drying-jet milling method: WO 91/16038) are known.
However, conventional powdered inhalations for transpulmonary administration prepared by the above-mentioned spray drying method or freeze drying-jet milling method are not necessarily ideal preparations for high-molecular-weight drugs such as peptides and proteins in particular. For example, as shown by the disclosure in WO 95/31479 that about 25% deactivation of interferon occurs during the spray drying process, it is anticipated that if the spray drying method is used, then proteins and the like will be deactivated in the manufacturing process and the activity of the drug will thus decrease.
No method is known which makes a high-molecular-weight drug into fine particles by a low air impact, the same as a low-molecular-weight drug.
Moreover, with both the spray drying method and the freeze drying-jet milling method, an operation is required in which the fine powder prepared is collected from the spray drying apparatus or jet milling apparatus and is subdivided and filled into vessels. It is thus inevitable that, accompanying this operation, problems will arise such as the yield of the preparation decreasing due to collection or filling loss and the cost rising correspondingly, and the preparation being contaminated with impurities. Moreover, in general it is difficult to subdivide and fill the powder in small amounts with good accuracy. If the spray drying method or the freeze drying-jet milling method, for which such subdividing and filling of small amounts in powder form is essential, is used, then it is thus necessary to establish a method of filling with small amounts and good accuracy of powder. In actual fact, details of a system, apparatus and method for filing with a fine powder are disclosed in U.S. Pat. No. 5,826,633.